MK-0448 (3 μM) shortened action potential duration at 90% repolarization from 318.2 to 265.3 ms in sinus rhythm preparations, but prolonged it from 218.3 to 275.0 ms in permanent atrial fibrillation.
Does the Kv1.5 blocker MK-0448 alter action potential duration and effective refractory period in human right atrial trabeculae from patients with different atrial rhythms?
MK-0448 exerts differential electrophysiological effects depending on the underlying rhythm, prolonging APD90 and ERP in permanent AF but shortening them in sinus rhythm, likely due to additional IKs blockade.
Absolute Event Rate: 265.3% vs 318.2%
p-value: p=<0.05
Selective blockers of the Kv1. 5 channel have been developed for the treatment of atrial fibrillation (AF), but little is known how these atrial-selective drugs affect human action potentials (APs). Therefore we have investigated the Kv1. 5 blocker MK-0448 (N-6- (1S) -1- (4-fluorophenyl) -2, 2-di (pyridin-3-yl) ethylpyridin-2-ylmethanesulfonamide) in right atrial trabeculae from patients in sinus rhythm (SR), permanent AF (> 6 months), and intermittent AF. MK-0448 blocked Kv1. 5 current in an expression system and concentration-dependently elevated the plateau phase of atrial APs. In SR preparations stimulated at 1 Hz, MK-0448 (3 µM) shortened action potential duration at 90% of repolarization (APD90) and effective refractory period (ERP), but in permanent AF preparations, MK-0448 prolonged APD90 and ERP. The effects of MK-0448 in intermittent AF resembled those in SR preparations. The APD-prolonging effect in AF preparations was more pronounced than with other IKur blockers, most likely due to the additional blocking effect of MK-0448 on IKs, a current that is present both in the atrium and ventricle. Block of IKs is probably more prominent in AF because of reduced repolarization reserve due to AF-induced remodeling.
Loose et al. (2014) studied Atrial fibrillation and sinus rhythm (n=44). MK-0448 vs. Pre-drug control was evaluated on Action potential duration at 90% repolarization (APD90) in sinus rhythm preparations (p=<0.05). MK-0448 (3 μM) shortened action potential duration at 90% repolarization from 318.2 to 265.3 ms in sinus rhythm preparations, but prolonged it from 218.3 to 275.0 ms in permanent atrial fibrillation.